Amyotrophic lateral sclerosis (ALS);
Lou Gehrig disease

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive degeneration of motor neurons in the brain and spinal cord. In 90% of patients, ALS is sporadic, with no clear genetic linkage. On the other hand, the remaining 10% of cases show familial inheritance, with mutations in SOD1, TDP43(TARDBP), FUS, or C9orf72 genes being the most frequent causes. In spite of such difference, familial ALS and sporadic ALS have similarities in their pathological features. Proposed disease mechanisms contributing to motor neuron degeneration in ALS are: impaired proteostasis, aberrant RNA processing, mitochondrial disfunction and oxidative stress, microglia activation, and axonal dysfunction.

Neurodegenerative disease

nt06410  Calcium signaling
nt06412  Unfolded protein response (UPR) signaling
nt06413  Autophagy
nt06414  Apoptosis
nt06415  PI3K signaling
nt06418  Oxidative phosphorylation
nt06419  Microtubule-based transport
nt06420  Ubiquitin-proteasome system
nt06421  Mitophagy
nt06423  Cytoskeletal regulation
nt06424  RNA processing
nt06464  Amyotrophic lateral sclerosis

(ALS1) SOD1; superoxide dismutase (mutation) [HSA:6647] [KO:K04565]
(ALS1) NEFH; neurofilament (deletion/insertion) [HSA:4744] [KO:K04574]
(ALS1) PRPH; peripherin (deletion) [HSA:5630] [KO:K07607]
(ALS1) DCTN1; dynactin 1 (mutation) [HSA:1639] [KO:K04648]
(ALS2) ALS2; alsin (mutation) [HSA:57679] [KO:K04575]
(ALS4) SETX; senataxin (mutation) [HSA:23064] [KO:K10706]
(ALS5) SPG11 [HSA:80208] [KO:K19026]
(ALS6) FUS; fusion (mutation) [HSA:2521] [KO:K13098]
(ALS8) VAPB; VAMP-associated protein (mutation) [HSA:9217] [KO:K10707]
(ALS9) ANG; angiogenin (mutation) [HSA:283] [KO:K16631]
(ALS10) TARDBP; TAR DNA binding protein (mutation) [HSA:23435] [KO:K23600]
(ALS11) FIG4; FIG4 homolog (mutation) [HSA:9896] [KO:K22913]
(ALS12) OPTN; optineurin (mutation) [HSA:10133] [KO:K19946]
(ALS14) VCP [HSA:7415] [KO:K13525]
(ALS15) UBQLN2 [HSA:29978] [KO:K04523]
(ALS16) SIGMAR1 [HSA:10280] [KO:K20719]
(ALS17) CHMP2B [HSA:25978] [KO:K12192]
(ALS18) PFN1 [HSA:5216] [KO:K05759]
(ALS19) ERBB4 [HSA:2066] [KO:K05085]
(ALS20) HNRNPA1 [HSA:3178] [KO:K12741]
(ALS21) MATR3 [HSA:9782] [KO:K13213]
(ALS22) TUBA4A [HSA:7277] [KO:K07374]
(ALS23) ANXA11 [HSA:311] [KO:K17095]
(FTD-ALS1) C9ORF72 [HSA:203228] [KO:K23609]
(FTD-ALS2) CHCHD10 [HSA:400916] [KO:K22759]
(FTD-ALS3) SQSTM1 [HSA:8878] [KO:K14381]
(FTD-ALS4) TBK1 [HSA:29110] [KO:K05410]
MAPT; microtubule-associated protein tau [HSA:4137] [KO:K04380]
GLE1 [HSA:2733] [KO:K18723]
(ALS/PDC) TRPM7 [HSA:54822] [KO:K04982]

Riluzole [DR:D00775]
Edaravone [DR:D01552]

Affected region: motor cortex, brain stem, spinal cord
Microscopic lesion: hyaline inclusions

PMID:30870681 (gene)

Mathis S, Goizet C, Soulages A, Vallat JM, Masson GL

Genetics of amyotrophic lateral sclerosis: A review.

J Neurol Sci 399:217-226 (2019)
DOI:10.1016/j.jns.2019.02.030

PMID:28980624 (gene)

Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH

Amyotrophic lateral sclerosis.

Nat Rev Dis Primers 3:17071 (2017)
DOI:10.1038/nrdp.2017.71

PMID:19251628 (ALS6)

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE

Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.

Science 323:1208-11 (2009)
DOI:10.1126/science.1165942

PMID:19251627 (ALS6)

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

Science 323:1205-8 (2009)
DOI:10.1126/science.1166066

PMID:19118816 (ALS11)

Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH

Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.

Am J Hum Genet 84:85-8 (2009)
DOI:10.1016/j.ajhg.2008.12.010

PMID:19081518 (drug)

Turner MR, Kiernan MC, Leigh PN, Talbot K

Biomarkers in amyotrophic lateral sclerosis.

Lancet Neurol 8:94-109 (2009)
DOI:10.1016/S1474-4422(08)70293-X

PMID:18802454 (ALS10)

Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

PLoS Genet 4:e1000193 (2008)
DOI:10.1371/journal.pgen.1000193

PMID:16924260

Pasinelli P, Brown RH

Molecular biology of amyotrophic lateral sclerosis: insights from genetics.

Nat Rev Neurosci 7:710-23 (2006)
DOI:10.1038/nrn1971

PMID:16503123

Gros-Louis F, Gaspar C, Rouleau GA

Genetics of familial and sporadic amyotrophic lateral sclerosis.

Biochim Biophys Acta 1762:956-72 (2006)
DOI:10.1016/j.bbadis.2006.01.004

PMID:16501576 (ALS9)

Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr, Hardiman O

ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis.

Nat Genet 38:411-3 (2006)
DOI:10.1038/ng1742

PMID:15952898 (ALS1)

Valentine JS, Doucette PA, Zittin Potter S

Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.

Annu Rev Biochem 74:563-93 (2005)
DOI:10.1146/annurev.biochem.72.121801.161647

PMID:15478096 (ALS4)

Kunst CB

Complex genetics of amyotrophic lateral sclerosis.

Am J Hum Genet 75:933-47 (2004)
DOI:10.1086/426001

PMID:15106121

Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF

DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).

Am J Hum Genet 74:1128-35 (2004)
DOI:10.1086/421054

PMID:11239414

Julien JP.

Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.

Cell 104:581-91 (2001)
DOI:10.1016/S0092-8674(01)00244-6

PMID:20428114 (ALS12)

Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H

Mutations of optineurin in amyotrophic lateral sclerosis.

Nature 465:223-6 (2010)
DOI:10.1038/nature08971

PMID:26213621

Yamashita S, Ando Y

Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis.

Transl Neurodegener 4:13 (2015)
DOI:10.1186/s40035-015-0036-y

PMID:19567404

Sieh W, Choi Y, Chapman NH, Craig UK, Steinbart EJ, Rothstein JH, Oyanagi K, Garruto RM, Bird TD, Galasko DR, Schellenberg GD, Wijsman EM

Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates.

Hum Mol Genet 18:3725-38 (2009)
DOI:10.1093/hmg/ddp300